3, 20 diketals derivatives of 9alpha-halo 16-hydroxy-hydrocortisone and cortisone



United States Patentc) 3,20 DIKETALS DERIVATIVES F 9a-HALO 16-HYDROXY-HYDROCORTISONE AND CORTISONE Josef Fried and Gordon H. Thomas,New Brunswick,

NJ., assignors to Olin Mathieson Chemical Corporation, New York, N.Y., acorporation of Virginia No Drawing. Application June 6, 1957 Serial No.663,913

13 Claims. I (Cl. 260-23955) This invention relates to the synthesis ofsteroids and has for its objects: (1) the provision of an advantageousprocess of preparing physiologically-active steroids of the9a-halo-16ot-hydroxy pregnene series; and (2) the provision of certainnew steroids useful either for their own physiological action or asintermediates in said process.

The process of this invention essentially comprises: (a) treating a3,20-diketalized 9a-halo-A -steroid of the pregnadiene series withosmium tetroxide, and (b) deketalizing the l6a,17a-dihydroxy steroidthus formed.

The novel compounds of this invention may be represented by the generalformula wherein one of the positions 4,5 and 5,6 is double-bonded, A isa divalent organic radical, such as lower alkylene (e.g. ethylene,propylene-1,2 and propylene-1,3), R and R together are either keto orOA-O-, wherein A is as hereinbefore defined, R is hydrogen, R' isB-hydroxy or together R" and R" is keto, X is halogen, and Y and Y arehydrogen or an acyl radical, especially the acyl radical of ahydrocarbon carboxylic acid having less than ten carbon atoms, asexemplified by the acyl radicals of the lower alkanoic acids (e.g.acetic, propionic and butyric acid), the monocyclic aryl carboxylicacids (e.g. benzoic and toluic acid); the monocyclic aryl lower alkanoicacids (e.g. phenacetic and B-phenylpropionic acid), the lower alkenoicacids, the cycloalkanecarboxylic acids and the cycloalkenecarboxylicacids.

The compounds of this invention are utilizable as intermediates in thepreparation of the corresponding 3,20-diketo derivatives (e.g. the9u-halo-l6a-hydroxyhydrocortisones, the 9a-halo-16a-hydroxycortisonesand esters thereof), which are disclosed in the application of JosefFried, Serial No. 646,969, filed March 19, 1957, (and in the literaturecited therein) as being physiologically active steroids.

a 2,929,814 Patented Mar r The first step in the process of thisinvention can be represented by the following equation:

OHsOY III This reaction is achieved by means of osmium tetroxide whichintroduces hydroxyl groups into both the 16 and 17 positions. Thereaction is preferably conducted in} an organic solvent for the steroid(e.g. benzene) in the presence of an organic base such a pyridine. Thereaction readily takes place at room temperature although any othernormal temperature may be employed.

The starting materials used in this reaction are dis-i diol-3,20-dione];the 21-esters of 9a-halo-A -pregnadi-- ene-21-ol-3,1l,20-trione3,20-diketals [c.g. 9a-flu0r0 (or chloro) -A -pregnadiene-21-ol-3,l1,20-trione acetate 3,20-bis-ethylene ketal]; and the 21-esters of9ahalo A -pregnadiene-11p,21-diol-3,20-dione 3,20-diketals [e.g.9a-fiu010 (or chloro)-A -pregnadiene-l15,21-

diol -3,20-dione 21-acetate 3,20-bis-ethylene ketal].

The reaction results in a 16a,l7a-dihydroxy derivative (Compounds A)containing in the 3,9,11,20 and 21 positions substituents correspondingto those in the startingmaterial. Thus, if the steroid reactant containsfree' keto groups in the 3 and 20 positions, a physiologicallyactive9a-halo-1ou-hydroxyhydrocortisone (or cortisone) is formed directly. If,however, a ketal is employed as the reactant, the product formed alsocontains the ketalgroup and one of the new steroids of this invention isprepared. This ketal intermediate .mustthenbe con-f Representativestarting materials include We to h f e ei t a m re t v describedhereinafter and as represented by the followiugequations:

To prepare Compounds B, Compound A, diketalized the 3,20-positions andesterified in the Zi -position, is hydrolyzed as by heating with adilute acid- (e,g.' dilute sulfuric acid), for. less than two. hours (egfor one one half hours) the reaction preferably being carried out in anorganic solvent (e.g. methano1 where in thediketal issoluble. Thereactionresults in deketalization. in the 3-position andv saponificationin the 21- position to yield the ZO-monoketalderivative (Come pounds B,Y and Y being hydrogen). If the reaction This reaction is preferablycarried out in the. presencev of-an organic base, such as pyridine. Ifonly an equivalent of acylating agent is present per molof. steroid, a 2l.-monoacy1ated derivative is obtained. If, however, at least. twoequivalents of acylatingagent are employed, a

1611,, ZI-diester is formed (e.g. Compounds B, Y'and Y'- beingv acylradicals).

If Compounds A, diketalized and esterified in the 21- position, arereacted with an acylating agent as describedabove, a 16u-ester isproduced, (Cqmpw lfllgQrY a Y'--being acyl" radicals). V w 7 as es-tsmelting point at about 262-265".

If an attempt is made to reduce a compound of structure A, containing aketo group in the 'll-position, by means of an alkali metal borohydride(e.g. sodium borohydride), the nature of the product will depend on theconditions thereon for the reaction. In most solvents the reactionproceeds to yield the expected llp-hydroxy derivative (with concomitanthydrolysis of the ester group). To prepare a compound of the structureA" having an llfl-hydroxyl group, free keto groups in the 3 and 20positions and free hydroxyl groups in the 160: and 21 positions, it ispreferred that the reduction of compounds of the structure A be eifectedby heating in a polar solvent (e.g. aque us methanol), deketalizationbeing subsequently effected by heating the reaction mixture afteracidification with a dilute acid (e.g. dilute sulphuric acid). If,however, the reaction is conducted in tetrahydrofuran, a cycloborateester is the initial product (see Example 5) which must then behydrolized by treatment with aqueous alkali ('e.g. sodium hydroxide) toyield the free 16a,17a-dihydroxy compound.

The following examples illustrate the invention (all temperature beingin centigrade):

EXAMPLE 1 V 9 -fl1go'ro-A pregnene-16 a,17 ,21 -m'ol-3,1 1 ,20-trione 21acetate 3,20-bis-et hylene ketal (IX) To a solution of 9a-fluoro-A-pregnadiene-21-ol-3,11- 20-trione ZI-acetate 3,20-bis-ethylene ketal(I) (1.28 g.) in benzene (25 ml.) and pyridine (1.2 ml.), is addedosmium tetroxide (582 mg). The solution is allowed to stand at roomtemperature for 18 hours, and is then stirred for 4 hours with water (68ml.), benzene (25 ml.), methanol (46 ml.), sodium sulfite (7 g.) andpotassium bicarbonate (7 g.). Chloroform m1.) is added and theprecipitate filtered off and washed with chloroform (100 ml.). Thefiltrate is washed twice with saline solution (2 x 20 ml.), dried oversodium sulfate, and evaporated to dryness in vacuo. Trituration of theresidue with methanol yields the triol (about 1.1 g.) withCrystallization from acetone-hexane affords an analytical sample atabout 279-282; [M 168 (c. 1.1 0 in CHCI Agar 2.90, 5,75, 5.86, 8.05,.t

Analysis.-Calcd. for C H 0 F: C, 61.81; H, 7.11; F, 3.62. Found: C,62,23; H, 7.13; F, 3.85.

Similarly, by substituting 9ot-chloro-A-pregnadiene-Zl-ol-3,1l,20-trione 21 acetate 3,20-bis-ethylene ketal(II), 9e-fluoro-A -pregnadiene-2l-ol-3,11,20-trione (III) 9e-chloro-A 1-pregnadiene-21-ol-3, 1 1,20-trione (IV) 9efluoro-A-pregnadiene-1-l}3,21-diol-3,20-dione (V), 9 t-chloro-A -pregnadiene-1lB,2l-diol-3,20-dione (VI) 9a-fluoro-A -pregnadiene-11,8,21-diol 3,20dione 2lacetate, 3,20-bis-ethylene ketal (VII), and 9e-ehlo1io-A n-pregnadiene-11e,2l-diol 3,20 dione 21- acetate 3,20-bis-ethylene ketal(VIII) for the, 9 u-fluoro-A -pregnadiene 21-ol-3,1l,20-trione21--acetate 3,20 hi57fithYlBHfi ketal in the procedure of Ex-,

ample 1, there is obtained respectively,

- dione 5 EXAMPLE 2 20-ethylene keta'l (XVII) EXAMPLE 3 9a-fluoro-A-pregnene 16a,17a,21 triol 3,11,20-trine 16,21-diacetate ZO-ethyleneketal (XVIII) A solution of 9e-fluoro-A -pregnene-l6a,17a,21-triol-3,1l,20-trione 20-ethylene ketal (XVII) in 2 ml. of pyridine and 0.7 ml.of acetic anhydride is left at room temperature for 18 hours. Thesolution is diluted with iced water and extracted with chloroform, theorganic layer then being washed with water, dried over sodium sulfateand evaporated under reduced pressure. Crystallization fromacetone-hexane gives the 20-ethylene ketal diacetate (about 41.7 mg),melting at about 187-190", lal +62 (c. 0.53 in CHCI M22; 232 m(e=17.700),' A23? 5.97, 616 This compound does not give thecharacteristic color reaction of an a-kCtOl with 2,3,5-triphenyltetrazolium chloride.

' Analysis-Cale. for C H O F (522.55): C, 62,08; .H, 6.75; F, 3.64.Found: C, 62.62; H, 6.63; F, 3.75.

EXAMPLE 4 :"9a fluoro-A pregnene-l6a,17a,21- triol 3,11,20-tri0ne16a-21-diacetate 3,20-bis-ethylene ketal (XIX) Similarly, 9a-fluoro-A-pregnene-l 15,160, 17a,21-tetrol- 3,20-dione 21-acetate3,20-bis-ethylene ketal (XIV) yields the 16,21-diacetate (XX).

EXAMPLE 5 9a-flu0r0-A -pregnene-11fi,16a,17a,21 tetrol 3,20-diam3,20-bis-ethylene ketal 16a,17a-cycl0b0rate ester A mixture of9a-fluoro-A -pregnene-16a,l7a,21-triol- 3,11,20-trione 21-acetate3,20-bis-ethylene ketal (IX) (200 mg.) and sodium borohydride (200 mg.)in tetrahydrofuran (2.5 ml.) and water (0.2 ml.) is stirred for 18 hoursat room temperature. The solution is then diluted with water ml.) andacidified to pH 6 by the addition of 8% sulfuric acid solution. Theprecipitate (about 166 mg.) is collected, washed with water and dried invacuo over phosphorus pentoxide. Crystalliza- 't't from acetone give theborate ester (about 110 mg.) with melting point greater than 300;

Analysis.-Calcd. for C H O BF (510.36): F, 3.72. Found: F, 3.28. I

Neutralization equivalent: 612. 1 f

The compound has the structural formula 9a-flu0r0-A -pregnene11p,I6a,17a,21 tetrol-3,20-dione 3,20-bis-ethylene ketal A stirredsolution of 9u-fluoro-A -pregnene-l1,3,16a, 17a,21-tetrol-3,20-dione3,20-bis-ethylene ketal 160:,17a, cycloborate ester (40 mg.) in 2Naqueous sodium hydroxide (6 m1.) and benzene (10 ml.) is refluxed undernitrogen for .3 hours. The solution is then diluted with 50 ml. ofwater, the aqueous layer then being separated and extracted with benzene(2 x '20 ml.). The benzene extracts are washed once with water, driedover sodium sulfate and evaporated to dryness in vacuo, leaving aresidue of 9a-fluoro-A -pregnene-11p,16a,17a,21-tetrol-3, 20-dione3,20-bis-ethylene ketal.

EXAMPLE 7 9u-flu0r0-A -pregnene-11;8,16a,17a,21 tetrol 3,20-dime3,20-bis-ethylene ketal 16a,21-diacetate Following the procedure ofExample 4 but substituting 9a fluoro-A -pregnene-llp,l6a,l7a,2l-tetrol3,20-di0ne 3,20-bis-ethylene ketal for the 9a-fluoro-A -pregnene-16e,17a,21-triol-3,11,20-trione 21-acetate 3,20 bis-ethylene ketal, there isobtained 9a-fluoro-A -pregnene-l13,160;

17a,21-tetrol-3,20-dione 3,20-bis-ethylene ketal 16a,21-di-' acetate.

EXAMPLE 8 (XIII) A solution of 9a-fiuoro-A -pregnene-16:1,17u,2l-triol-3,11,20-trione 2l-acetate 3,20-bis-ethylene ketal (IX) (100 mg.) andsodium borohydride (100 mg.) in meth-' anol (10 ml. and water (2 ml.) isrefluxed for 18 hours. The mixture is diluted with water (30 ml.) andextracted with chloroform, the organic layer then being washed once withwater, dried over sodium sulfate and evaporated to dryness in vacuo. Theresidue is taken .up in methanol (5 ml.) and 8% aqueous sulfuric acid,(0.5 ml.) and the solution refluxed for one hour. Water is addedand thesolution is extracted with chloroform. Evaporation of the chloroform invacuo followed by crystallization of the residue from ethanol yields thetetrol (about 20 mg.) melting at about 208-215 Recrystallization'from 95alcohol afiords a pure sample melting at about 250 and having aninfrared spectrum identi-. cal with that of an authentic specimen.

EXAMPLE 9 9otuor0-A -pregnene-16aJ7a,21-triol- 3,11 ,20-trione (XI) Asolution of 9a-fluoro-A -pregnene-16a,l7a,2l-triol- 3,11,20-trione2l-acetate 3,20-bis-ethylene ketal (IX) mg.) in methanol 10 ml.) and 8%sulfuric acid (1 ml.) is refluxed for 3 /2 hours. The mixture is dilutedwith water and extracted with chloroform, the organic layer then beingwashed once with water, dried over sodium sulfate and evaporated todryness in vacuo. The residue (M.P. about 220-231) consists of the 21-triol. v j I amen 7 EXAMPLE 1 oQa-fluOrO-M-pregrtene-I6a,]7a,21-tri0l-3,11,20- trione 1 601,21-diacetate (XXI) 9m fluoro A pregnene 16m,17a,21 triol 3,11,20- trione(XI) (80 mg.) is dissolved in pyridine (3 ml.) and acetic anhydride (1ml.) and allowed to stand at room temperature for 18 hours. Iced wateris added to the reaction mixture and the steroids are extracted withchloroform. The chloroform extracts are then washed with Water, driedover sodium sulfate and the solvent removed in vacuo. The residue (about70 mg.) on crystallization from acetone-hexane gives a pure sample ofdiacetate melting at about 224-227,

CHzOY wherein R is hydrogen, R is ,B-hydroxy and together R" and R' isketo, X is selected from the group consisting of chlorine and fluorine,and Y and Y are each selected from the group consisting of hydrogen andthe acyl radical of a hydrocarbon carboxylic acid having less than tencarbon atoms.

2. A compound selected from the group consisting of the ll-monoester and16a,2l-diester of 9a-halo-A -pregnene-l6o;,l7.rx,21-trio1-3,l1,20-trione3,2--diketa1 and a, hydrocarbon carboxylic acid having less than tencarbon atoms, wherein the halo radical is selected from the groupconsisting of chloro and fluoro.

3 The 2l-ester of 9ot-halo-A -pregnene-1661,17 11,21-triol-3,11,20-trione 3,20-diketal and a hydrocarbon carbogrylic acidhaving less than ten carbon atoms, wherein the halo radical is selected.from the group consisting of. chloro and fiuoro.

4. 90 -.fiuoro A pregnene 16ot,17u,21 triol 3,11,, 2 0-trione 21-acetate3,20-bis-ethylene ketal.

5. 9a halo A pregnene 11fi,16a,17a,21 tetrol- 3,20-dione 3,20-diketal,wherein the halo radical is selected from the group consisting of chloroand fluoro.

6. 9a fluoro A pregnene 11,B,ll6oc,17a,2l tetrol- 3,20-dione3,20-bis-ethy1ene ketal.

7. 9a halo A pregnene 16a,17a,21 triol 3,11, ZO-trione 20-ketal, whereinthe halo radical is selected from the groupconsisting of-chloro andfiuoro.

8. 90a fluoro A pregnene 16a,17a,21 triol 3,11, ZQ-trione ZQ-ethyleneketal.

' 9;. 9nrfluoro A pregnene 11B,16a,17a,21 tetrol- 3,20-dione3,2Q-bis-ethylene ketal 16a,l7a-cycloborate, ester.

10. A compound selected from the group consisting of the 2 1-monoesterand 16a,2l-diester of 9ot-halo-A-pregnene-16a,17u,21-triol-3,l'1,20-trione 20:ketal and a hydroearboncarboxylicacid having less than ten carbon atoms, whereinthe haloradical is selected from the group consisting of chloro and fluoro.

11. 9e fluoro n 'pregnene 15w, 17:1,21 triol- 3,11520-trioneIGeJI-diacetate ZO-ethylene ketal.

12. In the process for preparing a compound selectedfrom .the groupconsisting of steroids of the formulae and 20 OHzOY I "'OH wherein R andR" together are selected from the group consisting of keto and -O-AO-,wherein A is a divalent organic radial, R" is hydrogen, R'" isfi-hydroxy, and together R" and R is keto, X is selected from the groupconsisting of chlorine and fluorine, and Y is selected from the groupconsisting of hydrogen and the acyl radical of a hydrocarbon carboxylicacid having less than. ten carbon atoms, the step which comprisesinteracting a compound selected from the group consisting of steroids ofthe formulae and wherein R, R, R", R'", X and Y" are as above-defined,with osmium tetroxide.

13. The process of claim 12 wherein the steroid reactant is 9a-fluoro-A-pregnadiene-Z1-01-3,l1,20-trione ill-acetate 3,20-bis-ethylene ketal.

No referencescited;

UNITED STATES PATENT OFFICE Certificate of Correction Patent No.2,929,814 March 22, 1960 Josef Fried et a1.

It is hereby certified that error appears in the printed specificationof the above numbered patent requiring correction and that the saidLetters Patent should read as corrected below.

Column 2, lines 5 to 17, the right-hand formula should appear as shownbelow instead of as in the patent:

CHQOY OsOa column 3, lines 25 to 38, the left-hand formula should appearas shown below instead of as in the patent:

column 4, line 47, for 62,23 read -62.23; column 5, line 30, for 5.56read -5.76-; line 35, for 62,08 read 62.08.

Signed and sealed this 18th day of October 1960.

Attest:

KARL H. AXLINE, ROBERT C. WATSON, Attestz'ng Ofioer. Commissioner ofPatents.

1. A STEROID SELECTED FROM THE GROUP CONSISTING OF THE 20-MONOKETALS AND3,20-DIKETALS OF A STEROID OF THE GENERAL FORMULA